Peptidylarginine Deiminase Inhibitor Application, Using Cl-Amidine, PAD2, PAD3 and PAD4 Isozyme-Specific Inhibitors in Pancreatic Cancer Cells, Reveals Roles for PAD2 and PAD3 in Cancer Invasion and Modulation of Extracellular Vesicle Signatures

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies with limited survival rate. Roles for peptidylarginine deiminases (PADs) have been studied in relation to a range cancers roles epigenetic regulation (including histone modification and microRNA regulation), cancer invasion, extracellular vesicle (EV) release. Hitherto though, knowledge on PADs PDAC limited. In current study, two cell lines (Panc-1 MiaPaCa-2) were treated pan-PAD inhibitor Cl-amidine as well PAD2, PAD3, PAD4 isozyme-specific inhibitors. Effects assessed changes EV signatures, including cargo (miR-21, miR-126, miR-221), cellular protein expression relevant pancreatic progression invasion (moesin), mitochondrial housekeeping (prohibitin, PHB), gene (deiminated H3, citH3). The found predominantly express PAD2 which furthermore expressed at higher levels Panc-1, compared MiaPaCa-2 cells. had strongest effects reducing Panc-1 capability, was accompanied by an increase moesin expression, be reduced associated aggressiveness. Some reduction, but not significant, also PHB while H3 deimination variable. signatures modulated response PAD treatment, observed inhibitor, followed PAD3 showing significant reduction pro-oncogenic miR-221) anti-oncogenic (miR-126). While elevating modulating negligible less effective. Compared cells, stronger modulatory inhibitors importantly showed strong correlating previous observations that cells display neuronal/stem-like properties. Our findings report novel isozyme regulatory PDAC, highlighting depending type subtypes, PDAC.